Resistance development relative to treatment with medicines represents a universal defense mechanism of microorganisms, animals and plants. In humans, this defence mechanism is found in tumors. Generally, multiplication (amplification) of specific genes leads to the development of resistance. This gene amplification causes the overproduction of a gene product that directly or indirectly reduces the effect of the drug. Resistance development of Plasmodia (pathogens of malaria), and Leishmania (flagellates as pathogens of cutaneous Leishmaniose i.a.) is based partly on the amplification of the same genes as in human tumors.
Proof that gene amplification in bacteria leads to resistances has been successful with Proteus bacteria, Escherichia coli, Streptococca and Staphylococca. All are important hospitalism germs and pathogens of urinary tract infections (Romero and Palacios, gene amplification and genome plasticity in procaryotes, Ann. Rev. Genet. 1997). The mechanism underlying gene amplification, recombination, can likewise lead to the development of resistance. This form of resistance development has been proved unequivocally without exception in all types of bacteria but also for human tumors and all organisms which have been examined to date.
Malaria is a collective term for infections by protozoa of the Plasmodium type. Due to increasing resistance of Plasmodia to chemotherapeutics and of Anopheles mosquitoes to insecticides, the situation is increasingly deteriorating. Both resistances can be caused by gene amplification/recombination.
4-aminoquinolines (Chloroquine, Amodiaquine, mepacrine and Sontaquine are used as antimalaria drugs. These are analogues of quinine. Furthermore, there are two groups of antifolates, on the one hand dihydrofolate reductase (DHFR) inhibitors (pyrimethamine and chloroguanide) and on the other hand the sulphones and sulphonamides. Resistances can therefore arise due to amplification of the DHFR gene (Cowman and Lew, 1989; Cowman and Lew, 1990; Tanaka et al., 1990a; Tanaka et al. 1990b; Watanabe and Inselburg, 1994). The amplification of “Multi-drug-resistance” genes is likewise of importance (Foote et al., 1989). The amplification of the pfmdr1 gene is connected for example to resistance to mefloquine, halofantrine and quinine (Wilson et al., 1989; Cowman et al., 1994). As a result of increasing resistance of the Plasmodia to chemotherapeutics and Anopheles mosquitoes to insecticides, the situation is increasingly deteriorating. Both resistances can be caused by gene amplification/recombination. The development of resistance of Plasmodia is intended to be prevented by the prevention of chemotherapy-induced gene amplification.
Leishmaniases are caused by Leishmania (intracellular parasitic protozoa of the Mastigophora class) and infectious diseases transmitted by Phlebotoma (sand mosquitoes). Resistances to a chemotherapy are based on the amplification of some genes which also play a role in chemoresistance of tumours (Ouellette and Borst, 1991; Grondin et al., 1998; Arana et al., 1998; Heimeur and Ouellette, 1998; Kundig et al., 1999). The development of resistance is intended to be prevented by preventing chemotherapy-induced gene amplification/recombination.
The use of 5-substituted nucleosides for inhibiting resistance development during cytostatic treatment is already known from DE 195 45 892.